Chronic Pain: A Nutrition and Natural Health Reference
1. Definition, Classification, and Scope
Chronic pain is defined as pain that persists or recurs for more than 3 months. In chronic pain syndromes, pain can be the sole or leading complaint and requires special treatment and care. This definition was formalized by the International Association for the Study of Pain (IASP) Taskforce for the Classification of Chronic Pain, which developed a new coding framework adopted in the World Health Organization's ICD-11.
The ICD-11, for the first time, proposes a coding system for chronic pain. This system contains one code for "chronic primary pain," where chronic pain is the disease itself, and six codes for chronic secondary pain syndromes, where pain developed in the context of another condition.
Chronic pain affects 1 in 5 people and persists because protective nociception is converted into maladaptive neural, immune, and psychological states.
Under certain conditions, pain can become maladaptive and persist as chronic pain. This pain serves no protective function and is described as pathological pain as opposed to physiological pain; it is then no longer a symptom of another disease, but a disease in its own right.
Major ICD-11 Categories of Chronic Pain
- Chronic primary pain: Pain in one or more anatomical regions that is not better explained by another diagnosis (e.g., fibromyalgia, chronic widespread pain, chronic primary headache).
- Chronic cancer-related pain: Pain caused directly by the cancer or its treatment.
- Chronic postoperative or post-traumatic pain: Persistent pain after surgery or tissue injury lasting beyond the expected healing period.
- Chronic neuropathic pain: The new classification lists the most common conditions of peripheral neuropathic pain, including trigeminal neuralgia, peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, and painful radiculopathy. Conditions of central neuropathic pain include pain caused by spinal cord or brain injury, post-stroke pain, and pain associated with multiple sclerosis.
- Chronic secondary headache or orofacial pain.
- Chronic secondary visceral pain: Chronic visceral pain is persistent or recurrent pain that originates from the internal organs of the head and neck region and the thoracic, abdominal, and pelvic cavities.
- Chronic secondary musculoskeletal pain: Chronic musculoskeletal pain is defined as chronic pain arising from musculoskeletal structures such as bones or joints. The burden of chronic musculoskeletal pain to individuals and societies is substantial, being the greatest cause of disability worldwide, affecting approximately 22% of the global population.
2. How Chronic Pain Presents
Chronic pain is a major source of suffering. It interferes with daily functioning and is often accompanied by distress. Its presentation is highly variable and shaped by the underlying mechanism, but several hallmark features appear across conditions.
Sensory Abnormalities
Chronic pain is characterized by abnormal sensitivity, which is due to the generation of pain in response to activation of low-threshold mechanoreceptive A-beta fibers that normally generate innocuous sensations. Three different processes in the spinal cord can account for this dramatic alteration in sensory processing: increased excitability, decreased inhibition, and structural reorganization.
Central sensitization generates an exaggerated response to painful stimuli (hyperalgesia) and contributes to pain elicited by normally nonpainful stimuli (allodynia). These two phenomena — hyperalgesia and allodynia — are cardinal features of many chronic pain states.
Neuroplastic Changes
Clinical findings suggest that pain hypersensitivity produces structural changes in the brain over time. These changes are, however, reversible upon pain relief.
The mechanism by which a damaging stimulus in the body is perceived as painful by the brain is a complex one which is not yet fully understood. The complexity of the process results from the nervous system not being a "hard wired" system, but exhibiting plasticity that enables it to modify its function under different conditions.
3. Body Systems Involved
The Peripheral Nervous System
Nociception refers to the detection of noxious stimuli by nociceptors, followed by transduction and transmission of the sensory nervous information from the periphery to the brain. Pain refers to the product of higher brain center processing; it entails the actual unpleasant emotional and sensory experience generated from nervous signals.
In chronic neuropathic pain, peripheral mechanisms are prominent: peripheral nerve lesion evokes stimulus-independent (ectopic) activity in nerve fibers. The autonomic nervous system may also be involved; in a small but significant proportion of chronic pain sufferers the pain has a definite sympathetic system element to it.
The Central Nervous System and Central Sensitization
NMDA and neuropeptide receptor activation produces a sharp increase in intracellular calcium, triggering signaling pathways and gene expression changes that promote a long-term shift in the activity of nociceptive circuits. This process — central sensitization — is a cornerstone mechanism in many chronic pain conditions, including fibromyalgia and chronic low back pain.
The Immune System and Neuroinflammation
Innate immune cells react at the lesion site, in the dorsal root ganglion, where the cell bodies of peripheral somatosensory neurons reside, and in the dorsal horn of the spinal cord. Microglial activation and the release of pro-inflammatory mediators further amplify pain signals within the spinal cord. The biopsychosocial model, with its emphasis on neuroimmune interaction and peripheral and central sensitization, captures these overlapping mechanisms.
Synthesizing cross-disciplinary evidence positions chronic pain as a systems disease requiring integrated, mechanism-based, and person-centered care. Defining the shared biological scaffold clarifies why traditional symptom-focused treatments frequently fail.
Endocrine and Psychological Systems
Psychological distress, mood, and cognitive processing are deeply intertwined with pain perception at a neurobiological level. A range of studies have shown that psychological and lifestyle factors are associated with musculoskeletal pain, and these factors also correlate with persistent systemic inflammation. Since systemic inflammation is also present in numerous conditions involving musculoskeletal pain, it is of interest to examine whether systemic inflammation mediates the relationship between psychological and lifestyle factors and musculoskeletal pain.
4. Contributing and Associated Factors
Studying the distribution and determinants of chronic pain allows us to understand and manage the problem at the individual and population levels. Targeted and appropriate prevention and management strategies need to take into account the biological, psychological, socio-demographic, and lifestyle determinants and outcomes of pain.
Biological Factors
- Age and Sex: Factors such as age, gender, and obesity collectively add layers of complexity to chronic pain experiences. Gender differences and the prevalence of chronic pain in aging adults emphasize the need for tailored approaches.
- Obesity: Elevated body mass index is independently associated with increased pain sensitivity and chronic pain prevalence, due in part to adipose-tissue-driven systemic inflammation.
- Comorbid Conditions: The association between chronic pain and physical comorbidities like cardiovascular disease, chronic obstructive pulmonary disease (COPD), and diabetes mellitus reveals shared risk factors and further highlights the importance of integrated treatment strategies.
- Pre-existing Pain Sensitivity: Variables such as central sensitization, preoperative pain, chronic widespread pain, preoperative sleep disorders, and preoperative anxiety have been found to be strongly associated with transition to chronic pain.
Psychological Factors
- Fear Avoidance and Catastrophizing: There is moderate certainty evidence that smoking, fear avoidance, poorer support networks, lower socioeconomic status, and high levels of pain are associated with development of chronic musculoskeletal pain.
- Anxiety and Depression: Maladaptive behavior strategies, general anxiety, functional limitation during the episode, smoking, and particularly physical work were also explicitly predictive of chronicity in low back pain. Several prognostic factors from the biomechanical, psychological, and psychosocial point of view are significant for chronicity.
Socioeconomic and Lifestyle Factors
- Socioeconomic Status: Low socioeconomic status presents barriers to effective pain care.
- Smoking: Smoking is a consistently identified modifiable risk factor for chronification across several systematic reviews.
- Sleep: Poor sleep was associated with greater pain and inflammation, while behavioral sleep interventions improved outcomes.
- Occupational Factors: Heavy physical work and prolonged physical exertion in occupational settings are significantly associated with chronicity.
- Persistence of Musculoskeletal Pain: Once chronic musculoskeletal pain is established, it is hard to treat, with 79–92% of people still experiencing it up to 12 years later.
5. Nutrients, Herbs, and Natural Ingredients
5.1 Omega-3 Polyunsaturated Fatty Acids (PUFAs)
Traditional Use
Traditional use of oily fish and fish oils as part of dietary regimens in coastal and Arctic populations has historically been associated with lower rates of inflammatory conditions, though systematic documentation of this as a deliberate pain intervention is limited in ethnobotanical literature.
Scientific Evidence
Although omega-3 fatty acids are known for their anti-inflammatory and immunomodulatory effects, current clinical evidence regarding their efficacy in pain management remains inconclusive. However, a 2025 systematic review and meta-analysis provides the most comprehensive synthesis to date.
Researchers searched four databases from inception to February 2025 with no language restrictions; forty-one randomised controlled trials (n = 3,759) met predefined criteria. Omega-3 fatty acids showed a moderate, statistically and clinically significant reduction in pain intensity with a standardized mean difference (SMD) of −0.55 (95% CI −0.76 to −0.34; I² = 87%). The relief was noticeable at 1 month (SMD = −0.27) and improved by 6 months (SMD = −0.83).
The benefits were significant for rheumatoid arthritis, migraine, and other mixed chronic pain conditions, but not for osteoarthritis or mastalgia.
Omega-3 fatty acid supplementation offers a clinically meaningful and time-dependent reduction in chronic pain, particularly at moderate doses and in certain disease contexts. Standardization of outcome measures, dose optimization, and long-term trials are needed to better define its role in pain management.
Evidence strength: Moderate — supported by a large meta-analysis of 41 RCTs, but high heterogeneity (I² = 87%) across included trials limits definitive conclusions. Effects vary by condition, dose, and duration.
5.2 Turmeric and Curcumin (Curcuma longa)
Traditional Use
Turmeric is a common spice in India and has been described in Ayurveda as a treatment for inflammatory diseases. In western herbalism, turmeric is primarily used as an anti-inflammatory agent. The active phenolic compounds responsible for most of its biological activity are the curcuminoids — principally curcumin, demethoxycurcumin, and bisdemethoxycurcumin.
Scientific Evidence
Turmeric has consistently been demonstrated to produce analgesic and anti-inflammatory effects in animal models and in clinical trials, and appears to have less serious adverse effects than many current analgesics.
A key mechanism studied involves inhibition of inflammatory enzymes. Curcumin has been found to limit the activity of several enzymes, including lipoxygenase and cyclooxygenase-2 (COX-2), that are involved in promoting and maintaining inflammation. By reducing the effects of these enzymes, curcumin may also reduce inflammation and the pain associated with it in conditions such as arthritis.
In a randomized, double-blind, placebo-controlled trial evaluating a water-dispersible turmeric formulation (250 mg/day, 150 mg curcuminoids), the formulation reduced VAS score from baseline (5.4 ± 0.9) to day 90 (3.8 ± 0.8) with a greater mean reduction than placebo (−1.5 ± 0.7 vs −0.6 ± 0.8, p < 0.0001).
The NCCIH states that a 2021 review found several studies highlighting the beneficial effects of turmeric and curcumin in different patent formulations for treating and preventing inflammatory and painful disorders including inflammatory bowel diseases, osteoarthritis, skin, and oral inflammation, as well as neuropathic pain. However, the reviewers noted that because of inadequate clinical trials, further high-quality studies are needed to firmly establish the clinical efficacy of this plant.
A major practical challenge is bioavailability; standard curcumin is poorly absorbed from the gastrointestinal tract, and various enhanced delivery formulations (e.g., with piperine from black pepper, or nano/micellar preparations) have been developed to address this.
Evidence strength: Preliminary to moderate — multiple small-to-medium RCTs and meta-analyses show benefit in osteoarthritis and joint pain, but many trials are short, use heterogeneous formulations, and carry methodological limitations. Further large, high-quality trials are needed.
5.3 Boswellia (Boswellia serrata)
Traditional Use
Boswellia serrata is a branching tree native to the mountainous regions of Northern Africa, India, and the Middle East. Boswellia is an herbal extract made from the gum resin or bark of the tree and can be taken orally or applied topically. Traditionally, boswellia has been used in Ayurvedic practices to improve arthritis, reduce inflammation and pain. Frankincense (boswellia resin) has also held traditional use in Middle Eastern and African medicine systems for centuries.
Scientific Evidence
Several studies have shown that taking boswellia orally may help reduce inflammation and pain associated with osteoarthritis, but larger, higher-quality studies are needed.
The NCCIH summarizes a 2014 Cochrane review concluding that while a few herbs such as ginger, avocado-soybean unsaponifiables (ASUs), and the Ayurvedic herb Boswellia serrata, taken orally, may have modest benefits for osteoarthritis symptoms, the overall evidence is weak.
A 2025 narrative review on lifestyle and supplements for joint pain noted that anti-inflammatory diets such as the Mediterranean diet were linked to lower inflammation and symptom severity, while supplements like curcumin, glucosamine, and Boswellia showed modest benefits with favorable safety.
Evidence strength: Weak to preliminary — existing RCTs are generally small and of short duration. Boswellic acids (particularly AKBA, acetyl-11-keto-β-boswellic acid) are the primary active compounds, and the evidence base, while promising, remains insufficient for firm clinical recommendations.
5.4 Ginger (Zingiber officinale)
Traditional Use
Historically, ginger has been used in Asian medicine to treat stomach aches, nausea, and diarrhea. Today, ginger is used as a folk or traditional remedy for post-surgery nausea; nausea caused by motion, chemotherapy, and pregnancy; rheumatoid arthritis; osteoarthritis; and joint and muscle pain.
Scientific Evidence
Based on available evidence, it is unclear whether supplementation of ginger is beneficial in treating rheumatoid arthritis, osteoarthritis, or joint and muscle pain. A 2020 systematic review and meta-analysis of seven trials found insufficient evidence to support the use of oral ginger compared with placebo in pain relief and function improvement in patients with knee osteoarthritis.
Evidence strength: Insufficient/inconclusive — promising mechanistic rationale (gingerols and shogaols as COX and LOX inhibitors) but current clinical trial data do not yet support definitive conclusions for pain endpoints. Larger, well-controlled trials are needed.
5.5 Vitamin D
Traditional Use
Vitamin D is not a traditional herbal remedy; its understanding as a nutrient with pain-related roles emerged from 20th-century nutritional science. Historically, sunlight exposure and dietary fat-soluble vitamins were understood to support bone and muscle health across many cultures.
Scientific Evidence
Vitamin D exerts anatomic, hormonal, neurological, and immunological influences on pain manifestation, thereby playing a role in the aetiology and maintenance of chronic pain states and associated comorbidities.
A systematic review of 14 RCTs covering fibromyalgia and chronic musculoskeletal pain found that in three studies (of which two had the best-quality evidence), a correlation between diffuse muscle pain and vitamin D (25OHD) deficiency was confirmed. Six studies, of which four had the best-quality evidence, demonstrated that appropriate supplementation may have beneficial effects in patients with established vitamin D deficiency.
Eight studies, of which six had the best-quality evidence, demonstrated that vitamin D supplementation results in pain reduction. The results suggest a possible role of vitamin D supplementation in alleviating the pain associated with fibromyalgia syndrome and chronic musculoskeletal pain, especially in vitamin D-deficient individuals.
More research is necessary to determine whether Vitamin D is useful in the treatment of various pain conditions and whether the effect is limited to patients who are deficient in Vitamin D.
Evidence strength: Moderate in deficient populations — evidence is strongest for the correction of deficiency in patients with fibromyalgia and chronic musculoskeletal pain. Effects in vitamin D-sufficient individuals are not well established.
5.6 Magnesium
Traditional Use
Magnesium has not been used as a traditional herbal pain remedy in a strict ethnobotanical sense, but dietary mineral traditions in many cultures emphasize mineral-rich foods. In modern natural health practice, magnesium supplementation (in forms such as magnesium malate or glycinate) has been widely adopted for muscle pain and fibromyalgia.
Scientific Evidence
Magnesium deficiency appears to be more common in patients with fibromyalgia, and deficiency is correlated with the presence of fibromyalgia symptoms. A literature review searched the Cochrane and PubMed databases for studies examining the relationship between magnesium and fibromyalgia. A total of 18 relevant articles meeting inclusion criteria covered two main aspects: the correlation between magnesium levels in the body and fibromyalgia, and the effect of magnesium supplementation on clinical parameters of fibromyalgia.
Evidence strength: Preliminary — the association between low magnesium status and chronic pain (particularly fibromyalgia) is consistently observed in observational studies, but high-quality RCT data on supplementation outcomes are limited. The evidence base does not yet support firm quantitative conclusions.
5.7 Glucosamine and Chondroitin
Traditional Use
Glucosamine and chondroitin are naturally occurring compounds in joint cartilage and connective tissue; they are not traditional botanical remedies but became widely used as dietary supplements from the 1990s onward, primarily for osteoarthritis.
Scientific Evidence
The evidence for glucosamine and chondroitin is heterogeneous. According to the NCCIH, the preponderance of evidence on glucosamine and chondroitin sulfate—taken separately or together—indicates little or no meaningful effect on pain or function.
A 2018 meta-analysis of 30 trials found more nuanced results: estimates between chondroitin and placebo showed that chondroitin could alleviate pain symptoms and improve function. Compared with placebo, glucosamine proved significant effect only on stiffness improvement. However, the combination therapy did not have enough evidence to be superior to placebo.
A 2025 systematic review using PRISMA methodology (PubMed and Web of Science) found that overall, the evidence suggests that glucosamine and chondroitin are generally effective and well-tolerated, particularly for managing osteoarthritis and joint pain. Glucosamine and chondroitin provide beneficial effects on efficacy, particularly in osteoarthritis and joint pain. These effects seemed especially positive when the two were used in combination rather than alone, suggesting a synergistic relationship.
Notably, a Cochrane review found efficacy for glucosamine sulfate, but this was specific to the Rotta brand and not noted when findings were pooled with research on other brands. Improvement in knee OA was in both pain and function. Glucosamine hydrochloride supplements have not shown efficacy in OA. Glucosamine sulfate has also been tested in chronic low back pain and showed no evidence of efficacy.
Evidence strength: Mixed and form-dependent — evidence favors chondroitin for osteoarthritis pain, and glucosamine sulfate (specific formulations) for stiffness. Neither has demonstrated benefit beyond joint osteoarthritis. The overall evidence base is modest and subject to significant methodological variability.
5.8 Palmitoylethanolamide (PEA)
Traditional Use
Palmitoylethanolamide (PEA) is a naturally occurring fatty acid amide which was first isolated and described in 1957 as N-(2-hydroxyethyl)-palmitamide. It is endogenous to the human body and found in foods such as egg yolk, peanuts, and soy lecithin. Its use as a supplemental agent for pain is entirely a modern development, primarily in European clinical research since the 1990s.
Scientific Evidence
Palmitoylethanolamide (PEA), a naturally occurring fatty acid amide, has demonstrated utility in the treatment of neuropathic and inflammatory pain. Emerging reports have supported a possible role for its use in the treatment of chronic pain, although this remains controversial.
A systematic review and meta-analysis of double-blind RCTs found that the pooled analysis favored PEA over control treatment, with an average pain intensity reduction of 1.68 (1.05–2.31, p = 0.00001) points on a standardized 11-point scale. The effect size favoring PEA was statistically significant (Z = 2.91, p = 0.004), although heterogeneity among included studies was high (I² = 93%).
The results of this systematic review and meta-analysis suggest that PEA is an effective and well-tolerated treatment for chronic pain. Further study is warranted to determine the optimal dosing and administration parameters of PEA for analgesic effects in the context of chronic pain.
Mechanistically, PEA exerts its effects primarily by interacting with peroxisome proliferator-activated receptor alpha (PPAR-α) and through other molecular pathways involved in neuroinflammation and immune responses.
Evidence strength: Promising but limited — positive pooled effect size in meta-analyses is notable, but very high heterogeneity (I² = 93%) weakens the certainty of conclusions. Most trials are small and of variable quality. European studies predominate; replication in larger, independently funded trials is needed.
5.9 S-Adenosylmethionine (SAMe)
Traditional Use
SAMe is an endogenous molecule involved in methylation reactions throughout the body and is not a traditional herbal remedy. Its use as an oral supplement for osteoarthritis and depression has been studied since the 1970s.
Scientific Evidence
SAMe may be a treatment option for osteoarthritis, but the evidence about its effectiveness and safety is unclear. A 2009 Cochrane review of 4 trials with 656 participants that compared SAMe with placebo was inconclusive.
Evidence strength: Insufficient — the evidence base is small and methodologically inadequate to draw firm conclusions.
6. Dietary and Lifestyle Factors
6.1 Anti-Inflammatory Dietary Patterns
Arthritis (and chronic pain more broadly) is a chronic condition worsened by systemic inflammation, inactivity, poor nutrition, and disrupted sleep. Emerging evidence suggests lifestyle interventions may target root causes of disease, offering a proactive approach to reduce pain and preserve function.
Anti-inflammatory diets, such as the Mediterranean diet, were linked to lower inflammation and symptom severity. A pilot intervention study found that increased anti-inflammatory food intake was correlated with improved physical characteristics, stress, and pain in assessed patients. Moreover, decreased consumption of pro-inflammatory foods was positively correlated with sleep satisfaction, and following an anti-inflammatory Mediterranean-style diet was associated with improved physical characteristics and quality-of-life in patients with chronic pain.
A 2025 systematic review and meta-analysis noted that anti-inflammatory diets significantly improve pain in rheumatoid arthritis compared with usual diets, and benefits for physical health-related quality of life are likely related to the benefits observed on disease-specific markers and may also include improved sleep, sustained satiety, and self-reported and functional pain.
Key dietary principles repeatedly identified in the literature for chronic pain include:
- High intake of vegetables, fruits, legumes, whole grains, and oily fish (as sources of omega-3 fatty acids).
- Use of olive oil as a primary fat source (Mediterranean pattern).
- Reduction of ultra-processed foods, refined carbohydrates, and high omega-6 vegetable oils.
- Dietary patterns that include anti-inflammatory foods and restrict certain pro-inflammatory foods (such as those containing excessive refined gluten or high sugar loads).
6.2 Physical Activity and Exercise
Clinical practice guidelines issued by the American College of Rheumatology strongly recommend aerobic exercise and/or strength training, weight loss (if overweight), tai chi, and a number of pharmacologic and nonpharmacologic modalities for treating osteoarthritis of the knee, hip, or hand. The guidelines conditionally recommend balance exercises, yoga, acupuncture, and other nondrug approaches such as self-management programs for managing knee osteoarthritis.
Resistance training and Tai Chi improved strength, mobility, and pain, with added benefits for balance. Evidence from fibromyalgia research also shows that recent systematic reviews and randomized clinical trials provide encouraging evidence that practices such as tai chi, qigong, yoga, acupuncture, mindfulness, and biofeedback may help relieve some fibromyalgia symptoms.
6.3 Sleep Quality
Poor sleep was associated with greater pain and inflammation, while behavioral sleep interventions improved outcomes. Sleep disturbance appears as both a consequence and an amplifier of chronic pain. Studies have been grouped into themes of influencing factors including sleep disturbances, obesity, and psychological factors as mediators of the relationship between lifestyle and chronic pain.
6.4 Psychological Stress Management
The bidirectional relationship between psychological stress and chronic pain is biologically mediated. A study in the Journal of Clinical Endocrinology and Metabolism found that plasma levels of TNF-alpha and IL-6 were elevated in patients with excessive daytime sleepiness, including those with sleep apnea and narcolepsy. Stress is also associated with decreased sleep and increased body mass due to the release of cortisol. Chronic stress increases glucocorticoid receptor resistance, which results in a failure to downregulate the inflammatory response.
6.5 Body Weight and Obesity
Excess adiposity drives systemic inflammation through the secretion of pro-inflammatory adipokines and cytokines from visceral fat tissue, creating a biochemical environment that lowers pain thresholds and perpetuates central sensitization. Weight reduction, through dietary change and physical activity, is therefore addressed as an integrated management strategy in international osteoarthritis guidelines.
7. Summary of Evidence Strength by Ingredient
- Omega-3 fatty acids (fish oil, EPA/DHA): Moderate evidence from a large 2025 meta-analysis (41 RCTs); statistically significant pain reduction particularly in rheumatoid arthritis and migraine. High heterogeneity limits precise conclusions.
- Curcumin/Turmeric: Preliminary to moderate evidence from multiple small–medium RCTs; consistent anti-inflammatory mechanism and benefit in osteoarthritis, but bioavailability challenges and trial heterogeneity remain limitations.
- Boswellia serrata: Weak to preliminary evidence; modest benefit for OA symptoms per a Cochrane review, favorable safety profile.
- Ginger: Insufficient clinical evidence for musculoskeletal pain per a 2020 meta-analysis; traditional use is well-documented.
- Vitamin D: Moderate evidence for deficient populations; benefit for fibromyalgia and chronic musculoskeletal pain is strongest when correcting true deficiency.
- Magnesium: Preliminary observational evidence links deficiency to fibromyalgia; RCT supplementation data are limited.
- Glucosamine/Chondroitin: Mixed evidence — chondroitin shows pain benefit in OA; glucosamine hydrochloride lacks efficacy evidence; combination results are inconsistent across studies.
- Palmitoylethanolamide (PEA): Promising evidence from multiple RCTs and meta-analyses; statistically significant pain reduction, well tolerated, but very high heterogeneity (I² = 93%) and the evidence base requires expansion.
- SAMe: Inconclusive; small evidence base.
References
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